1. Field of the Invention
The present invention relates to the field of weight reduction and maintenance of body weight. More specifically, the present invention provides a composition that is particularly suited for the long term management of weight in general, and chronic obesity in particular, that is effective and lacks undesirable side effects produced by other known treatments.
2. Description of the Background
There is an ever increasing concern with personal weight and appearance. Diets and weight loss programs are extensively advertised that have varying degrees of effectiveness, and utilized by a large segment of Western society, even by persons with weights in the normal range. There is, therefore, a continuing search for new and effective means to facilitate weight loss.
Obesity, on the other hand is a real disease with consequences to the general health of a person. Originally presumed to result from simple overeating or the combination of overeating with inactivity, it is more and more being considered the result of a combination of a genetic predisposition with a poor diet and exercise habits. It has been suggested that the predisposition to obesity is associated with a defect in the sympathetic nervous system which manifests itself as a high efficiency in food intake. In normal persons, food intake results in a thermogenic response, that is, an increase in body metabolism in which the caloric content of the food is expended as heat. Some studies suggest that persons with a genetic predisposition to obesity are metabolically "more efficient" than lean persons, and store excess caloric energy as body fat. In obese persons, thermogenic defects may make a significant contribution to weight gain in the absence of a controlled food intake since calories which are not expended as heat are stored as excess weight.
Although there are concurrent opinions on the intense need for the treatment for obesity and its related disease processes, the role of medications being used for its treatment is controversial. In many chronic conditions such as hypertension, diabetes, heart disease, hyperlipidemia, etc., the absence of a "cure" for the misregulation by the organism is considered acceptable by the medical community. The irony is, of course, that while the relation of the exacerbation of these diseases by obesity is well documented, "intervention treatments" of these diseases are widely accepted by the medical community whereas the treatment of the disease of obesity is mostly overlooked.
In fact, obesity is clearly a clinical condition where the absence of medication to achieve a long term cure is unacceptable. The belief that short term interventions will cure a chronic condition has hampered the development of medications and methods for producing and maintaining weight loss. However, substantial research and development on medications for weight loss and control of body weight has occurred in the field of anorexia. The majority of these anorexiant agents have received a negative image due to their classification as schedule II, III and IV, and their potential for dependence and abuse.
In addition to this, it has been shown that a high resting metabolic rate (RMR) is associated with metabolically active tissues. Thus, the RMR, and therefore the total energy expenditure, can be expected to decrease as the body cell mass diminishes during a program of weight reduction. This is commonly known as a slowing of the metabolic rate in response to dieting, which results in a plateau in the dieter's weight after an initial period where weight loss occurs. A significant complication of weight loss is the loss of a high percentage of lean body mass (and the associated decrease in metabolic rate) as opposed to the loss of body fat. The rate of weight loss, in effect, decreases with time when an individual is adhering to a diet in which energy intake is reduced. This has been attributed to the decrease in the RMR (energy expenditure) that occurs when the energy intake is restricted and may be attributed to the following factors.
(1) Loss of lean body mass, which results in a decreased RMR. PA1 (2) Lower thermogenic effect of food related to the lower energy intake.
This decrease in RMR, whether due to a genetic thermogenic defect or the consequence of a hypocaloric diet for weight loss, will produce the undesirable consequence of decreasing thermogenesis and the individual's caloric burning capacity.
It is evident that for obesity to occur, the energy intake must exceed the energy expended. Most pharmacological approaches to the treatment of obesity and methods of weight loss primarily focus on lowering the energy intake of the obese patient and resort to anorectic drugs that modify the metabolism of brain neurotransmitters involved in appetite regulation.
Various pharmaceutical compositions have been developed with the purpose of stimulating thermogenesis and thereby inducing weight loss. U.S. Pat. No. 5,019,594 provides a method of decreasing appetite by administering a composition containing ephedrine or other indirect acting sympathomimetic drugs and tyrosine or a tyrosine precursor. Ephedrine, an indirect sympathomimetic agent, is said to stimulate thermogenesis in laboratory animals, presumably by acting on their brown adipose tissue. In theory, the catecholamines activate thermogenesis in the brown adipose tissue of animals by binding to the animal's adrenergic receptors. Numerous studies have been published on the thermogenic response of humans and mammals to ephedrine treatment. The anorectic effect of ephedrine has also been investigated in rats. Ephedrine, however, used alone, was shown not to produce elevated blood pressure and tremors.
The thermogenic response elicited by ephedrine, methoxyphenamine, yohimbine, tranylcypromine, amitriptyline, iprindole and theophylline was studied in various mice and rat models, and found to differ with the respective drugs and the animal models used. For example, in mice made obese by a chemical lesion in the hypothalamus, all the drugs with the exception of theophylline caused a reduction in body fat without loss of body protein. All six drugs with the exception of theophylline caused a reduction in body fat without loss of body protein and produced a state of negative energy balance by means of a thermogenic effect. In contrast, in mice made obese by feeding a high protein, high fat diet, all seven drugs caused a negative energy imbalance. In genetically obese mice, only ephedrine and tranylcypromine were found to have any thermogenic activity. Similar variabilities in their physiological effects was seen in the rat models. The activity of thermogenic drugs in humans has been postulated to involve brown adipose tissue, as well. However, the proposed mechanism of action has never been verified in humans.
The affect of combinations of ephedrine with additional compounds such as caffeine, was also studied. In 1972, a composition containing ephedrine, caffeine and phenobarbital was noted as inducing loss of appetite and weight loss in humans. This composition, popularly known as the "Elsinore pill" was widely prescribed. However, serious side effects such as cutaneous reactions (tremors) were reported with this composition. Ephedrine/caffeine compositions without phenobarbital have also been investigated to reduce the side effects of the Elsinore pill. However, patients receiving this "modified Elsinore pill" continued to suffer from tremors similar to the effects seen with the Elsinore pill. More recent studies of the thermogenic effect in humans of a mixture of ephedrine and methylxanthines, such as caffeine and theophylline, have been reported by Dulloo and Miller (American J. Cain. Nutrition 43:388 (1986) and International J. Obesity 10:467 (1986)). These studies suggest that ephedrine/methylxanthine mixtures are more effective than ephedrine given alone. Methylxanthines are reported as potentiating the thermogenic anti-obesity effect of ephedrine and leading to normalization of body weight and body composition. However, other publications suggest that caffeine has no potentiating effect on the action of ephedrine. More recently, U.S. Pat. No. 5,055,460 disclosed the use of a composition containing caffeine, ephedrine and aspirin for weight reduction. The thermogenic effect of ephedrine/ethylephrine was reported to give inconclusive results. Aspirin, on the other hand, appears to potentiate the thermogenic effect of ephedrine.
Insulin is widely known to be one of the most powerful anabolic hormones in the body and the primary driver of amino acids and glucose into muscle cells. In muscle tissue, insulin initiates the transport of glucose, mineral ions and amino acids, and also regulates the synthesis and degradation of macromolecules. Insulin, in addition, decreases muscle catabolism during exercise which allows greater gains from intense exercise. It has been found that increased insulin activity affects tissues, and in particular muscle tissue, in a manner that promotes increased protein synthesis and muscle growth. Although insulin is primarily known for its ability to promote tissue uptake of blood sugar, i.e., glucose, it exerts a number of other important physiological effects, as well. These effects include increased synthesis and retention of protein in skeletal muscle and other tissues, stimulation of activated immune cells, enhanced brain uptake of tyrosine and tryptophan (precursors for important brain neurotransmitters), reduced output of free-fatty acids from adipose stores, accelerated potassium uptake by cells, and increased metabolic rate. Additionally, insulin mediates the thermogenic effect of carbohydrates which typically cause an increase in the metabolic rate following the absorption of dietary carbohydrates. Such mediation occurs through insulin activation of fat burning in "brown fat". Insulin is also required for proper thyroid function, and stimulates the "sodium pump", an enzyme that regulates ion movements and accounts for a significant fraction of the metabolic energy burned everyday. Studies have indicated a tendency for mature adults to lose sensitivity to insulin. A sedentary lifestyle, excess weight, and an over-refined diet (i.e., low fiber, low chromium, high in sugars) all contribute to a decreased insulin sensitivity. Studies have also found that individuals with impaired insulin sensitivity are at risk for high blood pressure, hypertension, heart disease and diabetes.
Numerous studies have found that vanadyl sulfate and chromium, when ingested, have properties that closely mimic as well as enhance many of the physiological effects of insulin. It has been found that these elements serve to both increase the effectiveness and enhance the anabolic effects of insulin. Supplementation of these elements into a normal diet has been shown to increase lean body mass without increasing body fat, stabilize blood sugar, i.e., glucose levels, increase the responsiveness of cells to insulin and lower blood fat levels. By their ability to potentiate the effects of insulin, both vanadyl sulfate and chromium have been found to enhance the entry of glucose (for energy) and amino acids (for protein synthesis) into muscle cells and inhibit the action of enzymes that catabolize the amino acids and proteins. It has further been found that these particular elements have cholesterol lowering, energy producing and anabolic promoting properties, which provide an optimal environment for anabolic development, weight/fat loss and energy output. Various cation salts have been tested for different applications. U.S. Pat. No. 4,315,927 discloses the formulation of essential metals as coordination complexes of picolinic acid, the pertinent portion of which is incorporated herein by reference. U.S. Pat. No. 5,013,752, on the other hand, proposes the administration of chromium picolinate in an edible food bar for the treatment of alcoholism. A mixture of chromium picolinate, chromium nicotinate glycinate, and vanadyl sulfate was disclosed in U.S. Pat. No. 5,164,384 as a dietary supplement for weight loss and cholesterol lowering.
The ideal drug for obesity was defined as being one that not only increases metabolic rate and causes loss of body fat but achieves these effects without a loss of body protein.
There is, therefore, a continuing search for new and more effective treatments to facilitate weight loss and for the treatment of long term management of obesity that lack the drawbacks of prior art treatments.